Beta chemokines have now been identified as potent soluble suppressors of macrophage-tropic HIV infection, in vitro. Studies of multiply exposed uninfected individuals have implicated the role of elevated beta chemokines in HIV resistance, in many cases, independent of genetic mutations in the chemokine receptor. Macaque studies have also suggested a role for beta-chemokines in vaccine induced protective immunity using a variety of vaccine candidates and live virus challenge. The close genetic and antigenetic relationship of HIV-2 with HIV-1 and the discordant biological phenotypes, led us to hypothesize that HIV-2 might afford protection from subsequent HIV-1 challenge. We have reported 52-74% protection in HIV-2 infected women that were observed for subsequent infection with HIV-1, our observation period has now been extended to over 13 years. In our quest for identifying the mechanism of this protection, we have recently demonstrated that approximately 60% of HIV-2 infected stimulated PBMCs are resistant to HIV-1 R5 infection compared with X4 viruses. This relative resistance was transferable, CD8 dependent and strongly correlated with beta chemokine production in the media. All relatively resistant cultures were rendered susceptible by addition of antibodies to beta chemokines. Our specific aims include in vitro and in vivo studies. 1. We will further identify and characterize the HIV-2 resistant phenotype the cellular sources of beta chemokines will be studied and each beta chemokine's contribution to the relative resistance phenotype will be assessed. 2. We will determine if beta chemokine secretion is specifically induced by HIV-2 infection, and correlate beta chemokine message with the secreted chemokine message with the secreted chemokine, in vitro. - we will determine if HIV-2 envelope/CD8 interactions contribute to an HIV-2 specific induction of beta chemokines and HIV-1 relative resistance. 3. We will determine if HIV-2 infected women continue to demonstrate protection from HIV-1 infection, partial protection will be evaluated with HIV-1 viral RNA l4evels as a secondary outcome. 4. We will determine the profile of beta chemokine message and protein in the evaluated HIV-2 infected women and study the association of beta chemokines with in vivo protection from HIV-1 infection.